Gene therapy strategies for rare monogenic disorders with nuclear or mitochondrial gene mutations

Wang, Yi; Hu, Li-Fan; Zhou, Tian‐Jiao; Qi, Lian-Yu; Liu, Xing; Lee, Jaiwoo; Wang, Fengzhen; Oh, Yu‐Kyoung; Jiang, Hu‐Lin

doi:10.1016/j.biomaterials.2021.121108

Cited by 13 publications

(3 citation statements)

References 145 publications

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“…Novel experimental strategies that fall into two broad categories, pharmacological and genetic approaches, are being investigated. Several recent reviews have focused on these emerging therapies [ 7 , 51 , 52 ]. Based on the current understanding of the effects of OXPHOS system flaws at the cellular level, several novel small molecules potentially capable of mitigating the consequences of hampered oxidative phosphorylation are in the preclinical developmental stage, and few of them have reached the clinical development stage [ 8 , 15 , 51 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”)

et al. 2022

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Background Methods The KHENERGYC trial will be a phase II, randomised, double-blinded, placebo-controlled (DBPC), parallel-group study in the paediatric population (birth up to and including 17 years). The study will be recruiting 24 patients suffering from motor symptoms due to genetically confirmed PMD. The trial will be divided into two phases. The first phase of the study will be an adaptive pharmacokinetic (PK) study with four days of treatment, while the second phase will include randomisation of the participants and evaluating the efficacy and safety of sonlicromanol over 6 months. Discussion Effective novel therapies for treating PMDs in children are an unmet need. This study will assess the pharmacokinetics, efficacy, and safety of sonlicromanol in children with genetically confirmed PMDs, suffering from motor symptoms. Trial registration clinicaltrials.gov: NCT04846036, registered April 15, 2021. European Union Clinical Trial Register (EUDRACT number: 2020–003124-16), registered October 20, 2020. CCMO registration: NL75221.091.20, registered on October 7, 2020.

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Section: Discussionmentioning

confidence: 99%

A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”)

et al. 2022

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“…We rst explored the feasibility of MLPers in treatment of LHON, which is a classical mtDNA-mutated mitochondrial disease with a high level of mitochondrial heterogeneity (Fig. 4) 47 . Using a set of testing indexes including mitochondrial protein contents, mtDNA copy numbers and mitochondrial mass, we showed that MLPers were administered to the Rot-treated animals harboring a high level of mitochondrial heterogeneity and produced a shift ranging from ~ 50% to less than 30% in heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Suppression of mitochondrial heterogeneity via engineered mitochondria for reversion of mitochondrial disease-related phenotypes

Wang

Liu

et al. 2022

Preprint

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Mitochondrial heterogeneity above the biochemical threshold (~50% damaged mitochondria load) induces the symptom manifest of multiple mitochondrial diseases without effective treatment. However, current mitochondria-targeted therapies related to mitochondrial heterogeneity regulation have yielded unsatisfactory clinical incomes due to the risk of damaged mitochondria carryover and the imbalance of mitochondrial homeostasis. Here, we show that engineered mitochondria (Mitochondria-Lipo@mParkin, MLPers) constructed by adhesion of mitophagy-mediated liposomes to the surface of exogenous mitochondria can supply healthy mitochondria via exogenous mitochondria and both remove damaged mitochondria via enhanced mitophagy. MLPers decrease the high level of mitochondrial heterogeneity to less than 30% which is obviously lower than their biochemical threshold, and lead to the reversion of disease-related phenotypes in two mouse models of tricky mitochondrial diseases (Leber’s hereditary optic neuropathy and idiopathic pulmonary fibrosis). The surface adhesion-engineered mitochondria are powerful tools for maintaining homeostasis of mitochondrial pool and offer a translational approach for pan-mitochondrial disease therapies.

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“…In recent years, nucleic acid drugs have shown promising therapeutic applications for many diseases through gene silencing, including cancers, [1,2] neurodegenerative diseases, [3][4][5] and some rare monogenic disorders. [6] However, inherent negatively charged phosphate backbones of nucleic acids hinder them from spontaneous cellular internalization. Auxiliary delivering systems are necessary, among which viral vectors and nonviral vectors are mostly studied during the past several decades.…”

Section: Introductionmentioning

confidence: 99%

Induced Self‐Assembly of Vitamin E‐Spermine/siRNA Nanocomplexes via Spermine/Helix Groove‐Specific Interaction for Efficient siRNA Delivery and Antitumor Therapy

Zhao,

Xu,

Wang

et al. 2024

Adv Healthcare Materials

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Gene therapy has been one of potential strategies for the treatment of different diseases, where efficient and safe gene delivery systems are also extremely in need. Current LNP technology highly depends on the packing and condensation of nucleic acids with amine moieties. Here, we attempt to covalently link two natural compounds, spermine and vitamin E, to develop self‐assembled nucleic acid delivery systems. Among them, the spermine moieties specifically interact with the major groove of siRNA helix through salt bridge interaction, while vitamin E moieties are located around siRNA duplex. Such amphiphilic vitamin E‐spermine/siRNA complexes can further self‐assemble into nanocomplexes like multi‐blade wheels. Further studies indicate that these siRNA nanocomplexes with the neutrally charged surface of vitamin E can enter cells via caveolin/lipid raft mediated endocytosis pathway and bypass lysosome trapping. With these self‐assembled delivery systems, we successfully achieve efficient siRNA delivery for Eg5 and Survivin gene silencing as well as DNA plasmid delivery. Further in vivo study indicate that VE‐Su‐Sper/DSPE‐PEG2000/siSurvivin self‐assembled nanocomplexes can accumulate in cancer cells and gradually release siRNA in tumor tissues and show significant antitumor effect in vivo. The self‐assembled delivery system provides a novel strategy for highly efficient siRNA delivery.This article is protected by copyright. All rights reserved

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Gene therapy strategies for rare monogenic disorders with nuclear or mitochondrial gene mutations

Cited by 13 publications

References 145 publications

A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”)

A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”)

Suppression of mitochondrial heterogeneity via engineered mitochondria for reversion of mitochondrial disease-related phenotypes

Induced Self‐Assembly of Vitamin E‐Spermine/siRNA Nanocomplexes via Spermine/Helix Groove‐Specific Interaction for Efficient siRNA Delivery and Antitumor Therapy

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